This project is aimed towards a more complete understanding of the assembly of envelope glycoprotein complexes of human cytomegalovirus (HCMV) that mediate attachment and entry into different types of cells in the body. HCMV is a ubiquitous pathogen that causes a wide range of severe diseases in individuals with undeveloped or compromised immune systems. Therapies are limited, and candidate vaccines have failed to elicit protective immunity. Recent advances have contributed to the view that the attachment/entry-mediating glycoproteins encoded by HCMV include those that provide ?universal? functions for entry into all cell types, and those that provide ?niche-specific? functions for entry into specific cell types. Infection of all cells by herpes viruses requires fusion mediated by the fusion glycoprotein, gB, and the cofactor gH/gL. For HCMV, gH/gL can be bound by either gO, or UL128-131. The gH/gL/gO complex appears to mediate gB fusion, whereas the gH/gL/UL128-131 complex facilitates infection of select cell types though a poorly characterized, non-fusion mechanism. The goals of the proposed project are to: 1) distinguish the functions and mechanism of the gH/gL complexes by analyzing a library of gH/gL mutants 2) analyze the cell type specific neutralizing activity of anti-gH antibodies 3) evaluate a panel human epithelial cells derived from different tissues as host cells for HCMV replication. replication.